Genetic analysis has identified 3 genes involved in early onset Alzheimer's disease, APP, and presenilin (PS) 1 and 2. Together mutations in these genes cause all autosomal dominant early onset disease. Apolipoprotein E(ApoE) is the only known risk factor for late onset disease although it does not explain all the familial clustering. Genetic analysis has led to the amyloid cascade hypothesis becoming the dominant theory underlying the etiology and pathogenesis of the disease, and this theory is being used to develop treatment strategies for the disease. A major project in our lab is to find the other genetic loci which contribute to disease and to determine how and whether variability at all loci affect amyloid metabolism. To this end, we are continually seeking to identify new mutations which lead to disease in the already-known genes, and also, in collaboration with investigators at Washington University and at Cardiff University (UK) we are carrying out genome screens in sibpairs to identify novel loci. Our work in this area has been the basis for our collaborators to make continually imporving cellular and animal models of AD. The work in these areas is also cited in this area